EP3174530B1 - Directly compressible polyvinyl alcohols - Google Patents

Description

The present invention relates to directly compressible co-mixtures for sustained-release tablet production containing polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs). The invention also provides a process for the preparation of corresponding directly compressible co-mixtures.

State of the art

Polyvinyl alcohol (PVA) is a synthetic, flexible polymer obtained by alkaline hydrolysis of polyvinyl acetate. The polyvinyl acetate in turn is obtained by a radical polymerization of vinyl acetate. By different chain lengths and different degrees of hydrolysis of the polyvinyl acetates can be obtained polyvinyl alcohols (PVAs) a variety of physical properties. The PVAs are particularly useful as film formers, adhesive gels and as viscosity modulators in a variety of applications, e.g. Paints, papers, textiles, cosmetics, etc. used.

Of particular interest to the pharmaceutical industry is the use of the PVAs in pharmaceutical preparations, e.g. in ophthalmics, as a film former for coated tablets, as a binder in granules or as a coating component in patches, as well as in drug delivery systems. Of particular interest is the use of various PVA types in the formulation of solid oral pharmaceutical dosage forms with prolonged drug release, e.g. in so-called "prolonged-release tablets". Delayed drug release is achieved in such polymer-containing pharmaceutical formulations in that the tablets do not dissolve directly in the presence of liquid, such as in the mouth or gastrointestinal tract, but swell and the active ingredient is released only gradually by diffusion.

By such galenically modified tablets, it is possible to administer the active ingredient from the dosage form in a controlled manner via a for a longer period of time in the body, thereby maintaining a therapeutically effective blood level of the drug over an extended period of time (several hours). The two main advantages of such retarded formulations - in contrast to tablets with an immediate release of active ingredient after ingestion - on the one hand the avoidance of unwanted possibly toxic blood / plasma levels of the API as well as a reduction in the frequency of use of the tablets (eg instead of 3 times / daily only one more time per day) and thus an improvement in the so-called "patient compliance" associated with an improved therapeutic result of the drug treatment.

However, known polyvinyl alcohols, which are specified for use in pharmaceutical formulations according to the various pharmacopoeias (Pharmacopoea Europaea, Ph. Eur., United States Pharmacopeia (USP), and the Japanese Pharmacopoeia (JP or JPE)) are not or only under special conditions directly tablettierbar by pressure. A particular problem in this context is therefore to produce tablets in a simple manner, which consist predominantly of corresponding PVAs as active substance carriers, wherein the active ingredient is homogeneously distributed. A direct tablettability of PVA-containing formulations can usually be achieved in the presence of higher proportions of further binders, such as lactose, and of lubricants and, if appropriate, further additives. Frequently, formulations in which PVAs are used as drug carriers are prepared in the presence of aqueous or alcoholic solutions. For example, it is known to prepare such sustained-release tablets by compressing the active ingredient and PVA in the presence of other additives after wet granulation. The latter is associated with the disadvantage that the required solvents must be removed again using energy.

task

As is apparent from the above, in order to achieve the desired retardation effects often swelling polymers are used as a matrix from which after moistening, for example, in the stomach and intestine of the Active ingredient is released in a time-controlled manner via diffusion and erosion processes and made available for resorption. Known examples of such polymers are, in particular, modified celluloses such as the hydroxypropyl methylcelluloses (HPMCs). However, the polyvinyl alcohols (PVAs) are also known in particular for such retardation effects. PVAs are used when, for example, there are incompatibility reactions between the active ingredient and HPMC, or when the HPMC types used show an unsatisfactory release profile of the active ingredient. For rapid tablet development with retardation effect, the galenic needs a swelling polymer, which is directly compressible and yet releases the drug time-controlled. However, powdery PVAs per se are not directly compressible - they provide tablets of insufficient hardness, which can not be handled in pharmaceutical practice, as they have, for example, an undesirable tendency to breakage or excessive abrasion.

It is therefore an object of the present invention to provide directly compressible Retardierungsmatrices that make time-consuming granulation unnecessary; d. H. Steps that consist of, for example, moistening with granulating liquids, mechanical mixing in mixing systems or fluidized bed plants, and post-drying processes for removing the granulating liquids and screenings, so that time and energy can be saved, but also expensive and time-consuming investments in special granulating plants. Object of the present invention is also to provide such advantageous directly compressible Retardierungsmatrices based on PVAs available. It is also an object of the present invention to provide a process by means of which PVAs or commercially available PVA grades can be converted into a directly compressible state.

Brief description of the invention

The present invention provides the galenic with a directly compressible prolonged release composition containing a co-blend of polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs). Preferably, such mixtures are the subject of the present invention, in which the polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs) used meet the requirements of the pharmacopoeias (Ph. Eur., USP and JPE.) According to the invention, corresponding directly compressible compositions can be polyvinyl alcohols (PVAs) of types 18 88-99 according to JPE and Ph. Eur. The object of the present invention is achieved in particular by directly compressible compositions containing polyvinyl alcohols (PVAs). which correspond to Ph. Eur. and which have been obtained by polymerization of vinyl acetate and by subsequent partial or almost complete hydrolysis of the polyvinyl acetate. Compositions which contain polyvinyl alcohols (PVAs) by 85% to 89% hydrolysis are particularly suitable In a special way, ent suitable compositions containing polyvinyl alcohols (PVAs), which are water-swellable resins according to USP by the formula

(C ₂ H ₄ O) _n

are characterized in which
n is an integer in the range of 500 to 5,000, and which has an average molecular weight in the range between 20,000 and 150,000 g / mol, which, according to Ph. Eur., has a viscosity in the range of 3-70 mPa.s. , (measured in a 4% solution at 20 ° C) and which have an ester number of not greater than 280 mg KOH / g (degree of hydrolysis> 72.2 mol%).

In direct compression molding compositions of improved properties according to the present invention, the PVAs and MCCs described are in a co-blend in a ratio ranging from 2: 1 to 1: 2 by weight, preferably in a ratio ranging from 2: 1 to 1: 1 ago. After intensive mixing, the co-mixtures of PVA with MCC found here have bulk densities in the range of 0.40-0.48 g / ml at tamped densities in the range of 0.55-0.63 g / ml.

In addition, a sustained-release prolonged-release tablet of several hours is also an object of the present invention, a tablet containing a co-blend of polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs) as characterized above. Surprisingly, it has been found that corresponding active ingredient tablets have delayed release of active compound of at least 2 hours, preferably for at least 6 hours, more preferably at least 8 hours, more preferably at least 10 hours, and most preferably at least 12 hours, depending on the active ingredient used and the mixing ratio of polyvinyl alcohols and microcrystalline celluloses.

In particular, it has been found that active ingredient-containing tablets containing a corresponding directly compressible composition in the form of a co-mixture in an amount of 1-99 wt .-%, preferably in an amount of 5-95 wt .-%, most preferably in a Amount of 10 - 90 wt .-% based on the total weight of the tablet containing the desired prolonged release of active ingredient. Advantageously, tablets with particularly high tablet hardnesses, which require surprisingly low ejection forces in the production process, can already be obtained with such compositions when low pressing forces are used. Already when using a pressing force of 19.5 kN tablets with a tablet hardness of 295.7 N can be obtained, which require only an ejection force of about 66.7 N. In addition, these tablets have only low friability of less than 1 wt .-%, preferably less than 0.5 wt .-%, in particular less than 0.1 wt .-%, as can be shown by suitable experiments.

Particularly well using the described co-mixtures delayed release tablets containing active ingredients of BCS class I either alone or in combination with other drugs by compression can be produced.

If there is a clinical need, however, also active ingredients of other BCS classes can be used directly with the method according to the invention compressible Dosagefromen be processed with a sustained release drug release.

The object of the present invention is further achieved by a process for the preparation of directly compressible prolonged release compositions comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs), wherein polyvinyl alcohol is ground to a fine powder and passed through a 800 sieve is sieved and intimately mixed with microcrystalline cellulose (MCCs) having an average particle size d _v50 in the range of 60 to 250 μm, and a bulk density in the range of 0.22 to 0.38 g / cm ³ .

Detailed description of the invention

Often, sufficient drug efficacy depends on consistent dosing and requires repeated dosing on a daily basis to maintain clinically adequate levels of blood levels of activity over a long period of time or avoid undesirable side effects. However, this multiple-use over the day is not desirable in patient compliance. Therefore, it is desirable for the administration of certain active ingredients to be able to provide tablet formulations that allow drug release to proceed slowly for hours, so that when taken regularly, a largely constant effective blood level is established throughout the day, but only once a day is required ,

Depending on the active ingredients to be used, the requirements for the particular composition are different. Depending on their chemical and physical properties, other excipients and tableting aids are to be used, since not every active ingredient is compatible with any tabletting excipient, or can be processed together on the basis of chemical and physical properties.

The bioavailability of drugs may be subdivided into a Biopharmaceutical Classification System (BCS) developed by Gordon Amidon in the United States in the mid-1990s and now part of both a US Food and Drug Administration (FDA) guideline and a European guideline Agency for the Evaluation of Bioequivalence of Medicinal Products.

For example, active ingredients of BCS class I are readily soluble active ingredients with a high permeation capacity. Their absorption is controlled only by the rate of gastric and defecation. For active ingredients belonging to this class but whose effectiveness is desired throughout the day, efforts are being made to develop formulations which will allow sustained, even release of active ingredient.

The Biopharmaceutical Classification System (BCS) describes relationships that play an important role in the oral administration of drugs. It is based on the work of G. Amidon and colleagues from 1995. The authors describe in this work that the oral bioavailability of drugs is influenced mainly by their solubility, dissolution rate and permeability through biological membranes ( Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995; 12: 413 .)

For BCS class 1 agents both solubility and permeability are high.

This means that if both the solubility and the permeability of the drug are high, it can be assumed that the absorption rate is mainly determined by the rate of gastric and defecation.

Since August 2000, the BCS system has been used for the approval of finished medicinal products by the US Food and Drug Administration (FDA). Under certain conditions, bioavailability and bioequivalence studies may be dispensed with when applying for the approval of the finished medicinal product (FAM) if it is demonstrated by application of the BCS system that the new finished medicinal product and an already authorized FAM of the same medicinal product must be bioequivalent. Then a waiver may be requested from the obligation to conduct these costly and in this case unnecessary bioavailability studies. For this purpose, the drug in the respective drug form must meet certain requirements with regard to the main parameters solubility, permeability and dissolution rate.

Solubility:

The highest dose of the drug must be completely dissolved in a maximum of 250 mL of an aqueous dissolution medium in a pH range between pH 1 and pH 7.5.

Permeability:

A drug will have high permeability if at least 90% of an administered dose is absorbed by the body. This must be demonstrated by appropriate data (e.g., mass balance studies).

Dissolution rate:

The dosage form must ensure rapid release of the drug. This must be proven by suitable in vitro release tests (either rotary basket or stirring blade method). At least 85% of the corresponding dose must be released within 30 minutes in three different release media (0.1 N HCL, buffer pH 4.5 and buffer pH 6.8).

A solution to the problem of providing a well soluble drug evenly over hours appears to be possible through the use of polymeric drug carriers, the latter slowly becoming a gel in the presence of physiological fluids such as saliva or gastric and intestinal fluids form and deliver the drug slowly and controlled by diffusion from the tablet matrix.

Here, polyvinyl alcohols (PVAs) are suitable, which are water-swellable resins as synthetic polymers and have excellent film-forming and emulsifying properties and form a gel in aqueous solutions. PVAs are according to USP by the formula

(C ₂ H ₄ O) _n

is characterized in which
n is an integer in the range of 500 to 5,000. Depending on the molecular size of these polymers and their chemical composition, their properties vary greatly, in particular with regard to water solubility, but also in terms of tablettability.
PVAs are made from polyvinyl acetate, whereby the functional acetate groups are partially or fully hydrolyzed to yield functional alcohol groups. As the degree of hydrolysis increases, the solubility of the polymer in aqueous media increases, but also the crystallinity and melting temperature of the polymer increases. In addition, the glass transition temperature varies depending on the degree of hydrolysis.
For example, a 38% hydrolyzed material has no melting point, but a glass transition temperature of about 48 ° C, whereas a 75% hydrolyzed material has a melting temperature of about 178 ° C, an 88% hydrolyzed material has a melting point of about 196 ° C and 99% hydrolyzed material has a melting point of about 220 ° C, but the polymer tends to decompose rapidly at a temperature above 200 ° C.

To prepare the compositions of the present invention, polyvinyl alcohols (PVAs) of types 18-88, 26-88 and 40-88 and any intermediate grades including type 28-99 of JPE or Ph. Eur. Can be used.

Although polyvinyl alcohols are soluble in water, they are almost insoluble in almost all organic solvents, with the exception of a few solvents, such as in ethanol with a slight solubility. These properties of the polymers make it very difficult to prepare tablet formulations in which PVAs are contained in a high proportion and which are directly tablettable.

For use in pharmaceutical formulations, polyvinyl alcohols of different degrees of hydrolysis are specified according to the various pharmacopoeias.

wobei EV der Ester-Zahl des Polymers entspricht. Unter der Esterzahl ist die Angabe der Menge Kaliumhydroxid in mg gemeint, die zur Verseifung der Ester in 1 g Probe erforderlich ist. Die Esterzahl berechnet sich aus der Differenz von Verseifungs- und Säurezahl.
Somit sind nach der Monographie des Europäischen Arzneibuches nur PVA-Polymere mit einer prozentualen Hydrolyse von mehr als 72,2% einsetzbar.The European Pharmacopoeia states that a permissible polyvinyl alcohol for use in pharmaceutical dosages must have an ester number of not more than 280 and an average molecular weight of between 20,000 and 150,000. The percentage of hydrolysis (H) can be calculated from the following equation: $$\mathrm{H}=\left(\left(100-\left(0.1535\right)\left(\mathrm{EV}\right)\right)/\left(100-\left(0.0749\right)\left(\mathrm{EV}\right)\right)\right)\times 100$$

wherein EV corresponds to the ester number of the polymer. By the ester number is meant the amount of potassium hydroxide in mg required to saponify the esters in 1 g of sample. The ester number is calculated from the difference between saponification and acid number.
Thus, according to the monograph of the European Pharmacopoeia, only PVA polymers with a percentage hydrolysis of more than 72.2% can be used.

According to the United States Pharmacopeia, polyvinyl alcohols suitable for use in pharmaceutical dosage forms must have a percentage degree of hydrolysis between 85 and 89% and have a degree of polymerization of 500 to 5,000. The degree of polymerization (DM) is calculated by the equation: $$\mathrm{DM}=\left(\mathrm{Molar\; Mass}\right)/\left(\left(86\right)-\left(\mathrm{12:42}\left(\mathrm{the\; degree\; of\; hydrolysis}\right)\right)\right)$$

A PVA that can be used in pharmaceutical formulations according to the European Pharmacopoeia Monograph is a PVA with a degree of hydrolysis between 72.2% and 90% resulting in both PVAs after the Ph.Eur. (Hydrolysis of more than 72.2%, but less than 90%, and those according to the USP (degree of hydrolysis between 85-89%).) These PVA grades have a molecular weight in the range of 14,000 g / mol to 250,000 g / mol.

As already described above, polyvinyl alcohols with a correspondingly high degree of hydrolyzation can be directly tabletted only under special conditions, ie. H. Granulation steps must be carried out in advance or the PVAs used must be mixed with further tabletting aids and readily compressible binders so that the proportion of polyvinyl alcohol in the overall composition is reduced.

It has now been found by experiments that not only the degree of hydrolysis of the polyvinyl alcohols used, and thus the crystallinity, plays a role for the good processability in tablet formulations, but also the physical properties and manifestations of the commercial PVA grades used.

Surprisingly, it has been found that the particle size of the PVA grades used has apparently an influence on the tablettability. In this connection, it has furthermore been found that, depending on the average particle size of the PVA powders, directly tablettable mixtures can be prepared in which the content of PVAs can be more than 60%.

A solution to this problem is therefore that a commercial, powdered polyvinyl alcohol is combined in a suitable manner with a very well compressible component, whereby a directly compressible, powdery product is obtained, which consists mainly of the PVA used. In the following, it is possible to produce tablets simply by mixing the product according to the invention with a desired active substance without further treatment and pressing with suitable pressure. Optionally, a few further additives, such as Lubricants and other additives are added. It is essential that no further treatment is required in order to be able to compress the resulting powder mixture into tablets.

Surprisingly, it has been found by experiments that it is possible to convert a wide variety of polyvinyl alcohols into a directly compressible tableting matrix by mixing ground, powdered PVAs with microcrystalline celluloses (MCC). It has been found particularly surprising in this connection that obviously only the MCCs are suitable for achieving such direct compression properties; other commonly direct compression promoting carriers, e.g. directly passable calcium hydrogen phosphates, including Fujicalin®, which can be directly tableted per se, directly compressible sorbitols (eg Parteck® SI 400), directly compressible mannitol (eg Parteck® M200) or directly compressible starches (eg Starch 1500), in combination with PVAs do not have this effect and do not lead to directly compressible powder blends with the PVAs, as their own research has shown.

By this surprisingly found effect, the galenic can now be provided with a directly compressible premix for tablet production consisting mainly of PVA, which leads to the acceleration of a development process of a new tablet formulation.

Microcrystalline cellulose (MCC) is a tableting aid in pharmaceutical manufacture and is preferably used as a drug carrier and is a component for almost any type of oral dosage forms such as tablets, capsules, sachets, granules and others.
In its pure form, microcrystalline cellulose (MCC) of the general formula (C ₆ H ₁₀ O ₅ ) _{n is a} white, free-flowing cellulose in powder form, which is commercially available with different grain sizes. In pharmaceutical quality, it meets the standards of the usual pharmacopoeias such as the Ph. Eur., The USP / NF or the JP. Among other things, microcrystalline cellulose serves as an indigestible, non-resorbable fiber for calorie-restricted foods, such as salad dressings, desserts and ice creams, as a release agent or as a carrier. As can be seen from the preceding description, it serves in pharmacy as a binder or carrier for tablet production. In this context, it has proven to be suitable for direct tableting and leads to hard tablets which have short disintegration times if suitably formulated.
MCC is derived from lignified parts of plants (not from waste paper). Here, the plant cellulose is freed with dilute hydrochloric acid at temperatures above 100 ° C of non-crystalline cellulose fractions. In other words, pharmaceutical grade MCC can be obtained by partial hydrolysis of high purity cellulose followed by purification and drying. Optionally, following hydrolysis, carboxylation can be used to improve the hydrophilic properties.

MCC is insoluble in water, alcohols and organic solvents. In water, MCC forms a three-dimensional matrix consisting of innumerable, insoluble microcrystals that form a stable thixotropic gel. The beneficial properties of MCC are also retained with temperature-related changes in the phase state, for example, during the transition to the freeze state or when heated to higher temperatures, so that MCC is well suited for ready mixes for further processing.

Commercially available types have proven to be suitable MCCs for achieving sufficient tablet hardness, the average particle sizes D _v50 in the range from 60 to 250 μm, preferably in the range from 80 to 200 μm, particularly preferably in the range from 80 to 150 μm, very particularly preferably in Range of 90 to 140 microns, determined by laser diffraction determination. In this case, such MCC types preferably have bulk densities in the range from 0.22 to 0.38 g / cm ³ , preferably in the range from 0.24 to 0.35 g / cm ³ , particularly preferably in the range from 0.28 to 0, 33 g / cm ³ . Suitable commercially available MCC grades which meet these criteria and are suitable for use in pharmaceutical formulations are, for example, Vivapur 102 (dried in the air stream, average particle size of about 100 μm, determined by laser diffraction, bulk density 0.28-0.33 g / cm ³ ), Avicel PH 102 (average particle size about 100 μm, bulk density 0.28 - 0.33 g / cm ³ ) and Emcocel 90M (spray dried, average particle size of about 100 microns, determined by laser diffraction, bulk density 0.25 - 0.37 g / cm ³ ).
However, other commercial products not mentioned herein which meet the described requirements can be used according to the invention described herein.

It is particularly surprising that the addition of suitable microcrystalline celluloses to the most varied PVA grades, in particular to PVAs having very different viscosities, results in directly compressible mixtures which consist predominantly of PVAs.

It has proved to be particularly advantageous if in the compositions according to the invention the ratio of the described PVAs and MCCs is in a range of 2: 1 to 1: 2 by weight, preferably in a ratio in the range of 2: 1 to 1: 1 lies. Such co-mixtures have been found to be particularly suitable for the production of sustained-release tablets. After intensive mixing, the co-mixtures of PVA found here with MCCs have bulk densities in the range of 0.43-0.45 g / ml at tamped densities in the range of 0.58-0.60 g / ml.

Due to the described advantageous properties of the combinations of PVA and MCC, the formulator in the pharmaceutical industry, but also in the food industry or in other technical fields a material at hand, which significantly simplifies the development effort for solid compressed dosage forms with prolonged release drug. All he needs to do is to mix his active ingredient to be retarded with the PVA-MCC combination, if necessary add a few excipients, especially lubricants and lubricants, and then press this mixture on a tableting machine. Due to the particularly good tabletting properties of this matrix, the development of prolonged-release tablets has also become possible with active substances which per se are actually considered not to be directly compressible and which would have to be granulated in the usual way. The use of the PVA-MCC matrix saves development time, equipment investment and leads to improved process reliability in development and production.

An advantageous side effect arises when using the co-mixtures according to the invention in the tabletting process, which consists in that the mixtures according to the invention lead to comparatively low ejection forces, whereby it is possible to work with significantly smaller amounts of lubricant than usual in tableting. Thus, instead of a usually 1% Magnesiumstearatzusatzes only about a quarter of this amount needed, possibly even less. Under special conditions, the addition of such lubricants can be dispensed with altogether. This requires an additional improvement in the interparticle binding forces, i. harder tablets are obtained with the same pressing force, whereby a more reproducible release of active ingredient can be achieved. The latter is due to the fact that the release is controlled essentially by the PVA content and the reduced addition of hydrophobic magnesium stearate exerts only a minor influence on the release behavior.

Furthermore, the present invention relates to a method for influencing the tableting properties of fine-grained PVA grades, in particular ground PVAs, which in themselves have only a low compressibility. It has been found by experiments that these PVAs can be converted into a directly pacable form by combination with MCCs.

Fine-grained PVAs are particularly suitable as retardation matrices, since they can generally be processed very well in order to produce more homogeneous mixtures with the active ingredient to be retarded. The latter is of particular importance for the single-dose accuracy "content uniformity" in order to always obtain the same amount of active ingredient in each individual tablet.

In addition, this type of formulation with fine-grained PVA grades has the advantage that the large surface areas of the fine PVA particles result in a more homogeneous gel layer formation after moistening in the gastrointestinal tract, resulting in the patient taking the tablets reproducible and possibly prolonged diffusion of the drug through this gel leads.

execution

To prepare the novel co-mixtures, suitable fine-grained polyvinyl alcohols (PVAs) are intensively mixed with microcrystalline celluloses (MCCs) and thus converted into co-mixtures which are outstandingly suitable as directly compressible tabletting matrices. This is particularly surprising, since blends of such PVAs with other perse which are also very readily compressible directly tablettable excipients of the market do not show this direct compression effect with the powdered PVAs. In the following experiments it can be shown by means of a formulation with powdered ascorbic acid as model active substance that PVA-MCC Co mixtures produced in this way are very suitable for the direct compression of poorly compressible active substances. Furthermore, it can be shown with the tablets produced which contain corresponding co-mixtures as excipients, that from such produced tablets, the active ingredient can be released controlled over a very long time. The experiments carried out have shown that corresponding active ingredient-containing tablets have sustained release of active substance of at least 2 hours, preferably over at least 6 hours, particularly preferred of at least 8 hours, more preferably of at least 10 hours, and most preferably of up to 12 hours, depending on used active ingredient and the mixing ratio of the polyvinyl alcohols and the microcrystalline celluloses.

Since in the context of the production of tablet formulations the term "directly compressible" is not defined as binding, in the present description the pressing behavior of a very readily directly compressible mannitol of the market (Parteck® M 200 (mannitol)), suitable for use as excipient EMPROVE ® Exp Ph Eur, BP, JP, USP, E 421, Article No. 1.00419, Merck KGaA, Darmstadt, Germany) was used as a benchmark for comparison. The aim is to directly compressible co-mixtures containing PVAs in larger quantities, in particular in terms of compressibility, the behavior of the Parteck® M 200 as close as possible.

The experiments carried out have found that active ingredient-containing tablets containing a composition according to the invention in the form of a co-mixture in an amount of 1-99 wt .-%, preferably in an amount of 5-95 wt .-%, most preferably in from 10 to 90% by weight, based on the total weight of the tablet, of the desired prolonged release of active ingredient. Advantageously, tablets with particularly high tablet hardnesses, which require surprisingly low ejection forces in the production process, can be obtained with such compositions, as desired, even when using low compressive forces. As has been found by attempts to produce placebos, tablets with a tablet hardness of 295.7 N, which require only an ejection force of about 66.7 N, are obtained even when using a pressing force of 19.5 kN. In addition, these tablets have only low friability, as can be demonstrated by suitable experiments.

The present invention thus provides a process for the preparation of directly compressible extended release compositions to produce a co-blend of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) wherein polyvinyl alcohol is a fine particle size powder D _v50 in the range of 50 to 260 μm, a bulk density in the range of 0.55 to 0.62 g / ml, a tamped density in the range of 0.72 to 0.85 g / ml and an angle of repose in the range of 35 to 38 And sieved through a 800 μm sieve, and the obtained microcrystalline cellulose (MCC) powder having average particle size D _v50 in the range of 60 to 250 μm and a bulk density in the range of 0.22 to 0.38 g / cm ^{3 is} mixed intensively. In this way, a directly compressible co-mixture with a bulk density in the range of 0.40 to 0.48 g / ml, a tamped density in the range of 0.55 to 0.63 g / ml and a angle of repose in the range of 35 to 38 °, which can be mixed with different agents as desired and compressed into tablets with a sustained release drug.

The examples given below disclose methods and conditions for the preparation of PVA-MCC-Co mixtures according to the invention. It is self-explanatory to those skilled in the art that other methods of grinding and mixing the starting materials are also available than those described herein.

From the examples, the particular advantages of these PVA-MCC combinations compared to the insufficient compressibilities obtained by PVA combinations with other - but particularly well tablettable - carriers are obtained.

When blending a PVA-MCC matrix according to the invention with a powdery ascorbic acid per se poorly compressible (as model active substance) and adding a very small amount of magnesium stearate as a lubricant can be obtained by simple direct tableting tablets sufficient hardness with little mechanical abrasion, which easily for further treatment eg be available for filling in blister packs or for the fracture-free removal from these blister packs by the patient. Corresponding tablets containing ascorbic acid show that prolonged ascorbic acid release from such PVA-MCC matrix tablets can be ensured over several hours.

List of pictures:

Fig. 1:

In FIG. 1 the compression force-hardness profiles are shown graphically according to the data from Table 1.

Fig. 2:

In FIG. 2 the press force-abrasion profiles are plotted according to the data from Table 1.

3:

In FIG. 3 the press force hardness profiles of the data are shown according to the compositions of Table 4.

4:

In FIG. 4 For example, the press force attrition profiles are graphically illustrated by the data in Table 4.

Fig. 5:

In FIG. 5 the release of ascorbic acid from prolonged-release tablets according to sample 1, characterized by data from table 9, is shown graphically.

Fig. 6:

In FIG. 6 is the release of ascorbic acid from prolonged-release tablets (Sample 2) characterized by data from Table 9, plotted.

Examples

The present description enables one skilled in the art to fully embrace the invention. Without further explanation, it is therefore assumed that a person skilled in the art can make the most of the above description.

If there are any ambiguities, it goes without saying that the cited publications and patent literature should be used. Accordingly, these documents are considered part of the disclosure of the present specification.

For a better understanding and clarification of the invention, examples are given below which are within the scope of the present invention. These examples also serve to illustrate possible variants. Due to the general validity of the described principle of the invention, however, the examples are not suitable for reducing the scope of protection of the present application only to these.

Furthermore, it is self-evident to the person skilled in the art that both in the given examples and in the remainder of the description, the amounts of components contained in the compositions add up to only 100% by weight or mol%, based on the total composition, and can not go beyond that, even if higher values could result from the indicated percentage ranges. Unless otherwise indicated,% values are in terms of% by weight or molar, with the exception of proportions given by volume.

The temperatures given in the examples and the description as well as in the claims are in ° C.

Apparatus / method for the characterization of the material properties

1. 1. Bulk density : according to DIN EN ISO 60: 1999 (German version) specification in "gImi"
2. 2. Tamping density : according to DIN EN ISO 787-11: 1995 (German version) -Input in "g / ml"
3. 3. angle of repose : according to DIN ISO 4324: 1983 (German version) specification in "degrees"
4. 4. Surface determined according to BET: evaluation and execution according to literature " BET Surface Area by Nitrogen Absorption "by S. Brunauer et al (Journal of American Chemical Society, 60, 9, 1983 ) Device: ASAP 2420 from Micromeritics Instrument Corporation (USA); Nitrogen; Weighing: approx. 3.0000 g; Heating: 50 ° C (5 h); Heating rate 3 K / min; Indication of the arithmetic mean of three determinations
5. 5. Particle size determination by laser diffraction with dry dispersion : Mastersizer 2000 with dispersing unit Scirocco 2000 (Malvern Instruments Ltd. UK), determinations at 1, 2 and 3 bar counter-pressure; Evaluation Fraunhofer; Dispersant RI: 1,000, Obscuration Limits: 0.1-10.0%, Tray Type: General Purpose, Background Time: 7500 msec, Measurement Time: 7500 msec, Performance in accordance with ISO 13320-1 and specifications of the technical manual and specifications of the equipment manufacturer; Data in Vol%
6. 6. Particle size determination by laser diffraction with wet dispersion: Mastersizer 2000 with wet dispersion unit Hydro 2000SM (Malvern Instruments Ltd. UK); Dispersion medium silicone oil thin liquid (manufacturer: Evonik Goldschmidt GmbH, Germany, name of the manufacturer: Tegiloxan3, article number of the manufacturer: 9000305); Dispersant RI: 1.403; Stirrer Speed: 2500 rpm; Tray Type: General Purpose; Background Time: 7500 msec; Measurement Time: 7500 msec; Obscuration limits: 7.0-13.0%; Execution according to ISO 13320-1 as well as the specifications of the technical manual and the specifications of the equipment manufacturer; Data in% by volume.
   Procedure: The suspension cell is filled with the low-viscosity silicone oil, the sample is added in portions until reaching the desired obscuration range (7.0-13.0%) and the measurement is started after a waiting time of 2 minutes.
7. 7. Particle size determination by dry sieving over a sieving tower: Retsch AS 200 control, Fa.Retsch (Germany); Substance quantity: approx. 110.00 g; Sieving time: 30 minutes; Amplitude intensity: 1 mm; Interval: 5 seconds; Test sieves with metal wire mesh according to DIN ISO 3310; Screen widths (in μm): 710, 600, 500, 400, 355, 300, 250, 200, 150, 100, 75, 50, 32; Indication of the quantity distribution per sieve fraction in the tables as "wt.% Of the initial weight"
8. 8. The tableting tests are as follows:
   The mixtures according to the compositions given in the experimental part are placed for 5 minutes in a sealed stainless steel container (capacity: about 2 l, height: about 19.5 cm, diameter: about 12 cm outside dimension) on a laboratory tumble mixer (Turbula T2A, Fa .Willy A. Bachofen, Switzerland).
   The magnesium stearate used is Parteck LUB MST (magnesium stearate vegetable) EMPROVE exp Ph Eur, BP, JP, NF, FCC Article No. 1.00663 (Merck KGaA, Germany) which was deposited on a 250 μm sieve.
   The compression to 500 mg tablets (11 mm punch, round, flat, with facet) is carried out on an instrumented Excenter tableting machine Korsch EK 0-DMS (Fa.Korsch, Germany) with the evaluation system Catman 5.0 (Fa. Hottinger Baldwin Messtechnik - HBM , Germany).
   Per tested pressing force (target settings: ~5, -10, ~20 and ~30 kN, actual effective measured pressing forces are given in the examples) at least 100 tablets are produced for the evaluation of the press data and the galenic figures.
   Tablet hardness , diameter and heights : Erweka Multicheck 5.1 (Erweka, Germany); Average data (arithmetic mean values) from 20 tablet measurements per pressing force. The measurements are made one day after the tablet is made.
   Tablet abrasion: Friability tester TA420 (Erweka, Germany); Device parameters and execution of the measurements according to Ph.Eur. 7th edition "Friability of uncoated tablets The measurements take place one day after tablet production.
   Tablet composition: Multicheck 5.1 (Erweka, Germany) with the balance Sartorius CPA 64 (Sartorius, Germany). Indication of the average value (arithmetic mean) from the weighing of 20 tablets per pressing force. The measurements take place one day after tablet production.
9. 9. Ascorbic Acid Release Test: The compressed tablets containing ascorbic acid (from the compression with 20 kN pressing force) are used in an in-vitro release apparatus from SOTAX (Allschwil, Switzerland) with the "Apparatus 2 (Paddle Apparatus)" described in USP 36 under <711>. and under the conditions described there for "extended-release dosage forms" (USP = United States Pharmacopoeia). Sampling takes place automatically via a peristaltic pump system with subsequent measurement in a Spectrometer 8453 (Agilent Technologies, USA) and a flow-through cuvette.
   The averaged values result from the release tests of 6 tablets containing ascorbic acid pressed with 20 kN pressing force.

Ascorbic acid used for tableting: L (+) - ascorbic acid, Ph Eur, USP, NF, Product 83568,290 (VWR, Germany)

Measuring equipment and measuring parameters:

1. 1.- Sotax AT7s release device equipped with Apparatus 2 (paddle apparatus according to USP 36)
   • Temperature: 37 ° C +/- 0.5 ° C
   • Speed of the paddle: 100 rpm
   • Volume of release medium per measuring vessel: 900 ml
   • Tablet mass: 500 mg
   • Total running time of the measurement: 720 min. (with sampling at 15, 30, 45, 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720 min.)
2. 2.- Tube pump for sampling: Sotax CY 7-50 (SOTAX, Switzerland)
3. 3.- Spectrometer 8453 (Agilent Technologies, USA)
   • Measurement at 244 nm in a 2mm flow cell
   • Evaluation via Excel
   • Preparation Medium: Dosa Prep X8 (DOSATEC GmbH, Germany)

Composition (in% by weight) of the release medium:

Potassium dihydrogen phosphate (Article No. 1,04873, Merck KGaA Darmstadt, Germany) 0.68% Titriplex III (Article No. 1,08418, Merck KGaA, Darmstadt, Germany) 0.02% Phosphoric acid 85%, (Article No. 1.00573, Merck KGaA Darmstadt, Germany) 0.20% Completely desalinated water 99.10%

Characterization of the materials used 1. Used PVA types and their properties: 1.1 Raw materials for grinding

• 1.1.1. PVA 4-88: polyvinyl alcohol 4-88, suitable for use as excipient EMPROVE® exp Ph Eur, USP, JPE, article no. 1.41350, Merck KGaA, Darmstadt, Germany
• 1.1.2. PVA 18-88: polyvinyl alcohol 18-88, suitable for use as excipient EMPROVE® exp Ph Eur, USP, JPE, article no. 1.41355, Merck KGaA, Darmstadt, Germany
• 1.1.3. PVA 26-88: polyvinyl alcohol 26-88, suitable for use as excipient EMPROVE® exp Ph Eur, USP, JPE, article no. 1.41352, Merck KGaA, Darmstadt, Germany
• 1.1.4. PVA 40-88: polyvinyl alcohol 40-88, suitable for use as excipient EMPROVE® exp Ph Eur, USP, JPE, article no. 1.41353, Merck KGaA, Darmstadt, Germany
• 1.1.5. PVA 28-99: polyvinyl alcohol 28-99, suitable for use as excipient EMPROVE® exp JPE, article no. 1.41356, Merck KGaA, Darmstadt, Germany
  These PVA types are present as coarse-grained, several millimeters large particles that can not be used in this form as a directly compressible tableting matrix.
  The large particles do not permit reproducible filling of the stamp dies and thus also no constant tablet weight at high rotational speeds of the (rotary) tabletting machines. In addition, only fine-grained PVAs can ensure a homogeneous distribution of the active ingredient in the tablet, without the occurrence of segregation effects; this is absolutely necessary for ensuring the single dose accuracy of the substance (content uniformity) in each tablet produced. In addition, only by a fine-grained PVA and the necessary for the reproducible retardation homogeneous gel formation can be ensured throughout the tablet body.
  For these reasons, the above-mentioned coarse-grained PVA types must be comminuted, ie ground, before being used as directly compressible retardation matrices.

1.2 Ground PVA types

• 1.2.1. Ground PVA 4-88, polyvinyl alcohol 4-88 Article No. 1.41350, Merck KGaA, Darmstadt, Germany
• 1.2.2. Ground PVA 18-88, polyvinyl alcohol 18-88 Item No. 1.41355, Merck KGaA, Darmstadt, Germany
• 1.2.3. Ground PVA 26-88, from polyvinyl alcohol 26-88 Item No. 1.41352, Merck KGaA, Darmstadt, Germany
• 1.2.4. Ground PVA 40-88, from polyvinyl alcohol 40-88 Item No. 1.41353, Merck KGaA, Darmstadt, Germany
• 1.2.5. Ground PVA 28-99, polyvinyl alcohol 28-99 Item No. 1.41356, Merck KGaA, Darmstadt, Germany

Marriage:

The grinding of the PVA types is carried out on an Aeroplex spiral jet mill Type 200 AS from Hosokawa Alpine, Augsburg, Germany under liquid nitrogen as cold grinding in the temperature range from 0 ° C to minus 30 ° C,

The resulting product properties of the ground PVA grades, in particular the powder indices such as bulk density, tamped density, angle of repose, BET surface area, BET pore volume and the particle size distributions, are shown in the following tables:

Bulk density. Tapped density. Angle of repose, BET surface area, BET pore volume:

(For details on the measuring methods see Methods) template Bulk density (g / ml) Tamped density (g / ml) Angle of repose (°) BET surface area (m ² / g) BET pore volume (cm ³ / g) PVA 4-88 * 0.61 0.82 35.1 .1308 0.0008 PVA 18-88 * 0.57 0.76 35.5 .1831 0.0011 PVA 26-88 * 0.56 0.74 35.5 .2045 0.0013 PVA 40-88 * 0.59 0.77 36.9 .1123 0.0009 PVA 28-99 * 0.58 0.76 37.7 0.2210 0.0016 * milled PVA

Particle distribution determined by laser diffraction with dry dispersion (1 bar counterpressure):

Data in μm (for details on the measuring method see Methods) Pattern PVA dv5 DV10 DV20 dv25 DV30 Dv50 dv75 Dv90 4-88 * 21.36 33.93 60.39 75.25 91.61 177.74 380.57 790.37 18-88 * 29.67 44.93 73.95 89.11 105.22 185.49 375.88 755.84 26-88 * 27.76 42.32 73.01 90.14 108.67 198.51 382.65 676.96 40-88 * 31.84 50.64 89.13 109.77 131.45 230.52 413.71 634.59 28-99 * 24.87 39.81 72.81 90,72 109.31 191.42 343.54 561.23 * milled PVA

Particle distribution determined by laser diffraction with dry dispersion (2 bar counter pressure):

Data in μm (for details on the measuring method see Methods) Pattern PVA dv5 DV10 DV20 dv25 DV30 Dv50 dv75 Dv90 4-88 * 19.09 30.21 52.69 64.83 77.87 143.83 279.64 451.94 18-88 * 26,90 40.38 65,30 78.08 91.55 159.10 321.46 607.64 26-88 * 24.59 36.93 61.67 75.05 89.33 157.79 286.17 434.23 40-88 * 31.03 49,47 88.54 110.06 132.79 235.87 430.35 686.10 28-99 * 24.27 39.63 74.31 93.13 112.51 196.45 350.21 570.12 * milled PVA

Particle distribution determined by laser diffraction with dry dispersion (3 bar backpressure):

Data in μm (for details on the measuring method see Methods) Pattern PVA dv5 DV10 DV20 dv25 DV30 Dv50 dv75 Dv90 4-88 * 18.35 29.27 51.25 63.09 75.77 139.46 269.80 425.62 18-88 * 24.55 36.60 57.91 68.48 79.45 132.37 246.56 393.59 26-88 * 25.17 38.18 64.35 78.47 93.57 167.41 317.16 514.18 40-88 * 32.81 53.33 96.27 119.6 1 144.21 256.31 463.67 717.76 28-99 * 22.33 35.92 65.94 82.31 99.37 174.84 305.50 454.03 * milled PVA

Particle distribution determined by laser diffraction with wet dispersion (in low viscosity silicone oil):

Data in μm (for details on the measuring method see Methods) Pattern PVA dv5 DV10 DV20 dv25 DV30 Dv50 dv75 Dv90 4-88 * 10.03 20.10 38.02 47.82 58.31 110.91 231.64 390.95 18-88 * 17.19 30,25 50.06 59.22 68.47 111.89 212.70 357.70 26-88 * 15.42 26.76 45.50 54.83 64.47 110.50 212.91 353.68 40-88 * 20.41 34,80 60.35 73.32 86.96 154.96 299.57 490.08 28-99 * 14.68 25.96 47.49 58.88 70,80 127.68 240.70 376.70 * milled PVA

Particle distribution determined by tower sieving:

2. Directly compressible carriers for the preparation of the blends with polyvinyl alcohols (milled)

• 2.1 Parteck® SI 150 (sorbitol), suitable for use as excipient EMPROVE® exp Ph Eur, BP, JP, JSFA, NF, E 420, article no. 1.03583, Merck KGaA, Darmstadt, Germany
• 2.2 Parteck® M 200 (mannitol), suitable for use as excipient EMPROVE® exp Ph Eur, BP, JP, USP, E 421, article no. 1.00419, Merck KGaA, Darmstadt, Germany
• 2.3 Parteck® Mg DC (magnesium hydroxide carbonate), heavy, suitable for use as excipient EMPROVE® exp Ph Eur, BP, USP, E 504, article no. 1.02440, Merck KGaA, Darmstadt, Germany
• 2.4 Fujicalin®, calcium hydrogen phosphate, anhydrous, DCPA, USP / NF, EP, JP (Fuji Chemical Industry Co., Ltd., Japan, obtained from SEPPIC GmbH, Cologne, Germany)
• 2.5 Lactose monohydrate (lactose), special tableting grade, suitable for use as excipient EMPROVE® exp Ph Eur, BP, NF, JP, Article No. 1.08195, Merck KGaA, Darmstadt, Germany
• 2.6 Starch 1500® (pregelatinized cornstarch) USP / NF, Ph Eur, JPE, IN 516247, Colorcon Limited, UK
• 2.7 Vivapur® 102 Premium, MCC (microcrystalline cellulose) Ph Eur, NF, JP, JRS Pharma, Rosenberg, Germany
• 2.8 Avicel® PH 102, MCC (microcrystalline cellulose) Ph Eur, NF, JP, FMC BioPolymer, USA
• 2.9 Emcocel® 90M, MCC (microcrystalline cellulose) Ph Eur, NF, JP, JRS Pharma, Rosenberg, Germany

3. Powdered ascorbic acid (used as a model drug)

L (+) - ascorbic acid, Ph Eur, USP, NF, Prod, 83568, 290, Ch ,: 11D180012, VWR, Germany

Particle distribution determined by laser diffraction with dry dispersion with 1 bar back pressure:

Details μm (for details on the measuring method see Methods) template dv5 DV10 DV20 dv25 DV30 ascorbic acid 27.63 57,03 103.64 123.02 141.50 template Dv50 dv75 Dv90 Dv95 ascorbic acid 215.48 335.67 467.13 552.17

Particle distribution determined by laser diffraction with dry dispersion with 2 bar back pressure:

Details μm (for details on the measuring method see Methods) template dv5 DV10 DV20 dv25 DV30 ascorbic acid 24.74 52.40 100.25 120.64 140.02 template Dv50 dv75 Dv90 Dv95 ascorbic acid 217.41 346.52 505.33 634.51

Particle distribution determined by laser diffraction with dry dispersion with 3 bar back pressure:

Details μm (for details on the measuring method see Methods) template dv5 DV10 DV20 dv25 DV30 ascorbic acid 11.85 24.55 62.66 82.02 100.81 template Dv50 dv75 Dv90 Dv95 ascorbic acid 177.57 304.33 451.03 558.34

Method:

1. 1. pressing the ground Polyvinyalkohole without any additives
2. 2. Preparation of the blends consisting of the various directly compressible carriers of the market with the ground PVA type 26-88
3. 3. compression of these blends and tablet characterization
4. 4. Description of the preparation of the co-mixtures of ground PVA 26-88 or 40-88 with the microcrystalline cellulose Vivapur® 102
5. 5. Production description of the blends of the two obtained under 4. Co-mixtures with powdered ascorbic acid
6. 6. compression of these blends and tablet characterization
7. 7. Examination of the delayed in vitro release of ascorbic acid from pellets obtained in this way

A) Test results: 1. pressing the ground PVAs without any additives

The ground PVA grades 4-88, 18-88, 26-88, 40-88 and 28-99 are pressed on a tableting machine Korsch EK 0-DMS without further additives (also no lubricant). Before pressing, the milled PVA grades are deposited by means of a 800 μm hand sieve (diameter 20 cm, company Retsch, Haan, Germany) in order to eliminate any agglomeration of PVA particles.

Parteck® M200 blended with 1% Parteck® LUB MST. Note: grouting the Parteck® M200 without any lubricant is not possible because of the resulting very high ejection forces. <b> Table 1: </ b> Tableting data of ground PVAs without additives Legend: A: Press force [KN] B: Tablet hardness after 1 day [N] C: tablet mass [Mg] D: tablet height [Mm] E: abrasion [%] F: ejection force (N) template A B C D e F Should is PVA 4-88 * 5 5.0 17.0 470.3 5.9 59.94 237.0 10 10.1 40.8 491.8 5.6 8.94 383.5 20 20.7 137.2 503.2 5.1 0.35 378.3 30 30.3 194.1 504.5 5.0 0.05 322.5 PVA 18-88 * 5 5.6 <10 409.7 5.9 100 246.4 10 10.1 23.0 493.7 5,7 18,90 354.4 20 19.9 89.1 499.9 5.2 1.03 382.7 30 29.9 151.1 504.0 5.0 0.14 355.7 PVA 26-88 * 5 7.3 23.9 444.7 5.6 23.37 318.2 10 10.7 51.1 488.8 5.4 4.98 345.7 20 19.2 129.5 492.9 5.0 0.46 327.7 30 30.7 191.8 490.9 4.8 12:06 275.7 PVA 40-88 * 5 7.6 20.5 443.1 5,7 39.93 296.7 10 10.1 33.0 490.3 5.6 9.67 321.7 20 18.8 150.8 506.6 5.0 0.65 317.7 30 28.5 151.4 504.6 5.0 0.12 282.9 PVA 28-99 * 5 4.7 <10 450.6 5.9 100 169.0 10 9.7 25.5 483.9 5.5 14.22 279.5 20 19.5 102.0 471.3 4.8 0.83 292.3 30 30.3 178.0 472.1 4.6 0.10 263.2 Parteck® M200 5 5.2 84.1 497.8 5.1 0.21 155.8 10 10.7 196.5 500.6 4.6 0.17 306.0 20 20.3 340.0 499.4 4.2 0.15 513.6 30 30.0 396.7 498.3 4.0 0.16 647.6 * milled PVA

In FIG. 1 the compression force-hardness profiles are shown graphically according to the data from Table 1.

In FIG. 2 the press force-abrasion profiles are plotted according to the data from Table 1.

Result:

1. a) no direct compression of the milled PVA types is possible, as tablets of insufficient hardness are obtained which do not allow safe handling (insufficient pressing force / hardness profiles)
2. b) the tablet abrasion, especially when using low compressive forces, is very high.
3. c) relatively low ejection forces ("self-lubricating effect") of the ground PVAs; theoretical advantage: stronger interparticle binding forces in the tablet; in the tested PVAs, however, this effect is not sufficient to obtain tablets with sufficient hardness and low abrasion.

2. Preparation of blends of direct-compression carriers with milled PVA grade 26-88

General description: Ground PVA 26-88 is deposited through a 800 μm hand screen. 300 g of this sieved product are weighed into a 2 l Turbula mixing vessel, 300 g of the appropriate excipient from A to I (see Table 2) are added and 5 min. mixed in a turbulam mixer T2A. <b> Table 2 </ b>: _ Composition of the examples AC and the comparisons DI composition 50% by weight PVA 50% by weight of carrier Example A PVA 26-88 * Vivapur® 102 Example B PVA 26-88 * Avicel® PH 102 Example C PVA 26-88 * Emcocel® 90 M Comparison D PVA 26-88 * Parteck® SI 150 Comparison E PVA 26-88 * Parteck® M 200 Comparison F PVA 26-88 * Parteck® Mg DC Comparison G PVA 26-88 * Fujicalin® Comparison H PVA 26-88 * lactose Comparison I PVA 26-88 * Starch® 1500 * milled PVA bulk density tapped density angle of repose Example A 0.43 g / ml 0.58 q / ml 36.4 ° Example B 0.44 g / ml 0.60 g / ml 35.3 ° Example C 0.45 g / ml 0.59 g / ml 35.6 °

3.Printing of these blends and tablet characterization

General description: per 498.75 g of the above-prepared co-mixtures of Examples AC or the DI comparisons are mixed in a Turbulamischgefäß with 1.25 g of magnesium stearate, another 5 min. mixed in a Turbulamischer T2A and tableted on an eccentric Korsch EK 0-DMS. <b><u> Table 4: Tableting data of the Co-blends Milled PVA 26-88 with excipients Legend: A: Press force [KN] B: Tablet hardness after 1 day [N] C: tablet mass [Mg] D: tablet height [Mm] E: abrasion [%] F: ejection force (N) template A B C D e F Should is Example A 5 5.1 76.8 498.4 5.4 0.26 91.3 10 10.2 171.4 502.1 4.8 0.05 91.8 20 19.5 295.7 503.4 4.5 0 66.7 30 30.0 354.5 502.5 4.4 0 58.6 Example B 5 4.9 70.2 501.8 5.4 0.49 85.9 10 9.6 153.1 506.1 4.9 0.16 87.3 20 18.4 267.3 506.6 4.5 0.07 61.1 30 28.6 325.1 506.8 4.4 0.04 52.1 Example C 5 4.9 71.0 494.2 5.5 0.39 90.9 10 10.2 159.6 497.0 4.9 0.06 92.3 20 20.0 273.6 496.8 4.5 0 64.8 30 30.4 318.0 498.2 4.4 0 57.3 Comparison D 5 5.0 31.0 498.2 5.4 3.86 66.6 10 9.9 86.0 502.8 4.9 0.37 94.1 20 20.5 170.0 503.6 4.5 0.08 78.6 30 30.8 188.5 503.4 4.5 0.06 64.8 Comparison E 5 5.0 17.1 493.0 5.6 17.05 84.2 10 10.0 51.5 499.8 5.1 1.12 138.8 20 20.3 137.6 501.3 4.7 0.21 162.9 30 29.7 178.0 500.1 4.6 0.16 150.9 Comparison F 5 6.1 22.1 482.7 5.6 7.30 107.7 10 10.2 50.1 501.4 5.2 1.28 133.2 20 20.9 137.4 505.0 4.7 0.13 149.0 30 31.2 224.3 501.6 4.5 0.01 144.0 Comparison G 5 5.0 22.7 492.7 4.9 9.55 121.0 10 10.3 48.6 495.0 4.5 1.42 148.5 20 20.6 115.2 494.5 4.1 0.27 126.2 30 29.6 161.6 492.1 3.9 0.10 102.0 Comparison H 5 4.9 <10 374.7 5.1 nb 57.3 10 10.2 16.7 488.2 5.0 100 98.4 20 19.9 50.2 495.3 4.6 2.00 127.3 30 29.0 77.4 497.3 4.5 0.50 135.1 Comparison I 5 5.0 <10 468.2 5.5 100 54.8 10 9.8 28.9 492.3 5.1 10.49 69.1 20 19.6 77.3 494.1 4.7 0.78 57.2 30 30.0 98.7 494.3 4.6 0.30 50.6 Parteck® M200 5 5.2 84.1 497.8 5.1 0.21 155.8 10 10.7 196.5 500.6 4.6 0.17 306.0 20 20.3 340.0 499.4 4.2 0.15 513.6 30 30.0 396.7 498.3 4.0 0.16 647.6

In FIG. 3 the press force hardness profiles of the data are shown according to the compositions of Table 4.

In FIG. 4 For example , the press force attrition profiles are graphically illustrated by the data in Table 4.

Result:

1. a) only the co-mixtures based on ground PVA 26-88 with the three tested MCC types (examples AC) provide tablets with sufficient hardness at all 4 tested pressing forces and come very close to the internal standard Parteck® M 200 in their compressibilities ; All other co-mixtures show significantly lower tablet hardness at the same press forces
2. b) Tablets based on Examples A-C, in particular at low compressive forces, show a reduced friability compared to the other matrices.

4. Production description of the co-mixtures of ground PVA 26-88 and ground PVA 40-88 with Vivapur® 102

Example A: Ground PVA 26-88 is deposited through a 800 μm hand screen. 300 g of the sieved product are weighed into a 2 l Turbula mixing vessel, mixed with 300 g of Vivapur® Type 102 and 5 min. mixed in a turbulam mixer T2A.

Example D: Ground PVA 40-88 is deposited through a 800 μm hand screen. 300 g of the sieved product is weighed into a 2 l Turbula mixing vessel, mixed with 300 g of Vivapur® Type 102 and left for 5 min. mixed in a turbulam mixer T2A. <b> Table 5: </ b> Composition of Examples A and D composition 50% by weight PVA 50% by weight of carrier Example A PVA 26-88 * Vivapur® 102 Example D PVA 40-88 * Vivapur® 102 * milled PVA bulk density tapped density angle of repose Example A 0.43 g / ml 0.58 g / ml 36.4 ° Example D 0.43 g / ml 0.59 g / ml 36.3 ° Legend: A: Press force [KN] B: Tablet hardness after 1 day [N] C: tablet mass [Mg] D: tablet height [Mm] E: abrasion [%] F: ejection force (N) template A B C D e F Should is Example A 5 5.1 76.8 498.4 5.4 0.26 91.3 10 10.2 171.4 502.1 4.8 0.05 91.8 20 19.5 295.7 503.4 4.5 0 66.7 30 30.0 354.5 502.5 4.4 0 58.6 Example D 5 5.0 64.2 500.4 5.4 0.49 76 10 10.3 146.9 505.7 4.9 0.15 90 20 20.1 247.4 506.0 4.5 0.08 62 30 32.0 296.6 506.0 4.5 0.07 91

5. Production description of the blends of the two obtained under 4. Co-mixtures with powdered ascorbic acid

Sample 1: 450 g of Co-mixture Example A are mixed with 150 g of ascorbic acid and 5 min. mixed in Turbulamischer T2A. On 498.75 g of this mixture is sieved over a 250 micron sieve 1.25 g of magnesium stearate and mixed for 5 minutes in Turbulamischer T2A

Sample 2: 450 g of Co-mixture Example D are mixed with 150 g of ascorbic acid and 5 min. mixed in Turbulamischer T2A. On 498.75 g of this mixture is sieved over a 250 micron sieve 1.25 g of magnesium stearate and mixed for 5 minutes in Turbulamischer T2A

6.Printing of samples 1 and 2 as well as tablet characterization

Table 8: Tableting data of patterns 1 and 2 Legend: A: Press force [KN] B: Tablet hardness after 1 day [N] C: tablet mass [Mg] D: tablet height [Mm] E: abrasion [%] F: ejection force (N) template A B C D e F Should is Pattern 1 5 5.3 34.8 501.6 5.1 3.19 73.4 10 10.0 74.4 504.6 4.7 0.61 88.2 20 20.0 140.0 504.5 4.3 0.21 88.0 30 30.5 173.7 505.2 4.2 0.14 87.6 Pattern 2 5 5.1 25.5 498.0 5.1 7.15 73.6 10 11.2 61.9 501.1 4.6 0.75 95.6 20 20.8 125.8 503.5 4.4 0.12 96.0 30 31.1 157.6 506.3 4.2 0.08 95.7

Result:

1. 1. Also in combination with a pulverulent ascorbic acid which is considered to be difficult to compress directly, tablets of sufficient hardness and low friability are obtained using the novel co-mixtures of Examples A and D which can be handled without difficulty; This makes it possible to dispense with the use of otherwise directly compressible Ascorbinsäuretypen
2. 2. The ejection forces of the mixtures with Example A and Example D are unusually low, even with only a very small amount of magnesium stearate added; This requires less wear of stamping tools and tableting machines.
3. 3. Due to the relatively small amount of magnesium stearate added, the desired sustained-release release is determined essentially only by the amounts and properties of the PVA used; the known disturbing influence of the hydrophobic magnesium stearate on the drug release behavior is minimized.

7. Examination of the delayed in vitro release of ascorbic acid from pellets obtained in this way

Table 9: Results of ascorbic acid release from sustained-release tablets of Sample 1 and Sample 2 (pressed at 20 kN pressing force) (In% by weight of the amount of ascorbic acid released based on an expected total amount of ascorbic acid / tablet, measurement of 6 tablets per sample) Sample 1 (tablets pressed with 20 kN pressing force) Sample 2 (tablets pressed with 20 kN pressing force) Time (min.) min Max Average min Max Average 0 0 0 0 0 0 0 15 14 20 17 15 18 16 30 21 28 24 22 25 24 45 26 34 30 27 32 30 60 31 40 35 32 37 35 120 46 57 51 46 53 50 180 60 72 65 58 66 63 240 71 84 77 67 77 73 300 81 91 86 72 82 78 360 89 98 93 78 89 85 420 94 101 97 86 93 90 480 97 103 100 90 96 94 540 98 104 101 96 102 99 600 98 104 101 98 103 101 660 98 104 101 99 103 101 720 98 104 101 100 103 102

In FIG. 5 the release of ascorbic acid from prolonged-release tablets according to sample 1, characterized by data from table 9, is shown graphically.

In FIG. 6 is the release of ascorbic acid from prolonged-release tablets according to sample 2, graphically represented by the data from table 9.

Result : a retarded in vitro release of the model compound ascorbic acid is possible over several hours

B) Conclusion

1. 1. The co-mixtures of milled PVA with MCC lead to very well directly tablettable tablet matrices. Even at relatively low compressive forces can produce tablets with sufficient hardness and mechanical stability.
2. 2. With these matrices per se effective as poorly tablettable active ingredients in a direct tableting process into tablets with good galenic properties, especially in terms of hardness and mechanical stability process.
3. 3. With the help of these matrices, direct-release tablets can be used to quickly and easily produce prolonged-release tablets with an active ingredient release that lasts for several hours.

Claims (18)

1. Directly compressible composition having extended release of active compound, comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs).
2. Directly compressible composition according to Claim 1, comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs), where the latter meet the requirements of the pharmacopoeias PhEur, USP or JPE.
3. Directly compressible composition according to Claim 1 or 2, comprising polyvinyl alcohols (PVAs) of grades 18-88, 26-88 and 40-88 and all grades in between in accordance with the requirements of the pharmacopoeias PhEur, USP or JPE, including grade 28-99 in accordance with the requirements of the JPE or PhEur.
4. Directly compressible composition according to one or more of Claims 1 to 3, comprising polyvinyl alcohols (PVAs) which conform to PhEur and which have been obtained by polymerisation of vinyl acetate and by subsequent partial or virtually complete hydrolysis of the polyvinyl acetate.
5. Directly compressible composition according to Claim 1, 2, 3 or 4, comprising polyvinyl alcohols (PVAs) which have been obtained by 85% - 89% hydrolysis.
6. Directly compressible composition according to one or more of Claims 1 to 5, comprising polyvinyl alcohols (PVAs) having an average relative molecular weight in the range between 20,000 and 150,000 g/mol which have a viscosity in accordance with PhEur in the range 3 - 70 mPa.s (measured in a 4% solution at 20°C).
7. Directly compressible composition according to one or more of Claims 1 to 6, comprising polyvinyl alcohols (PVAs) which have an ester value of not greater than 280 mg of KOH/g (degree of hydrolysis > 72.2 mol%).
8. Directly compressible composition according to one or more of Claims 1 to 7, which comprises polyvinyl alcohols (PVAs) as water-soluble resin, which is characterised in accordance with USP by the formula
   
           (C₂H₄O)_n,
   
   in which
   n denotes an integer in the range from 500 to 5,000.
9. Directly compressible composition according to one or more of Claims 1 to 8, comprising PVA and MCC in a co-mixture in a ratio in the range 2 : 1 to 1:2, preferably in a ratio in the range 2 : 1 to 1:1.
10. Directly compressible composition according to one or more of Claims 1 to 9, characterised in that the co-mixture of PVA with MCCs has a bulk density in the range 0.40 - 0.48 g/ml with tapped densities in the range 0.55-0.63 g/ml.
11. Tablet comprising a composition according to one or more of Claims 1 to 10 which, even on use of a pressing force of 19.5 kN, results in tablets having a tablet hardness of 295.7 N and requires an ejection force of about 66.7 N.
12. Active-compound-containing tablet having extended release of active compound over several hours, comprising a co-mixture of polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs) in accordance with one or more of Claims 1 to 10.
13. Active-compound-containing tablet according to Claim 12, comprising a directly compressible composition in the form of a co-mixture in accordance with one or more of Claims 1 to 10 in an amount of 1 - 99% by weight, preferably in an amount of 5 - 95% by weight, very particularly preferably in an amount of 10 - 90% by weight, based on the total weight of the tablet.
14. Active-compound-containing tablet according to Claim 12 or 13, which has a particularly high tablet hardness, even on use of low pressing forces, and requires low ejection forces.
15. Active-compound-containing tablet according to one of Claim 12 to 14, which exhibits a low friability of less than 1% by weight, preferably of less than 0.5% by weight, in particular of less than 0.1% by weight.
16. Active-compound-containing tablet according to one or more of Claims 11 to 15 having delayed release of active compound of at least 2 hours, preferably over at least 6 hours, particularly preferably of at least 8 hours, especially preferably of at least 10 hours, and very particularly preferably of at least 12 hours.
17. Active-compound-containing tablet according to one or more of Claims 11 to 16 having delayed release of active compound, comprising active compounds in BCS class I, either alone or in combination with other active compounds.
18. Process for the preparation of directly compressible compositions according to one or more of Claims 1 to 11 having extended release of active compound, comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs), characterised in that polyvinyl alcohol is ground to give a fine-grained powder and sieved through an 800 µm sieve, and mixed intensively with microcrystalline cellulose (MCCs) having an average particle size D_v50 in the range from 60 to 250 µm, and a bulk density in the range from 0.22 to 0.38 g/cm³.

Images